title: Alternative 5' untranslated regions are involved in expression regulation of human heme oxygenase-1.
abstract: The single nucleotide polymorphism rs2071746 and a (GT)n microsatellite within the human gene encoding heme oxygenase-1 (HMOX1) are associated with incidence or outcome in a variety of diseases. Most of these associations involve either release of heme or oxidative stress. Both polymorphisms are localized in the promoter region, but previously reported correlations with heme oxygenase-1 expression remain not coherent. This ambiguity suggests a more complex organization of the 5' gene region which we sought to investigate more fully. We evaluated the 5' end of HMOX1 and found a novel first exon 1a placing the two previously reported polymorphisms in intronic or exonic positions within the 5' untranslated region respectively. Expression of exon 1a can be induced in HepG2 hepatoma cells by hemin and is a repressor of heme oxygenase-1 translation as shown by luciferase reporter assays. Moreover, minigene approaches revealed that the quantitative outcome of alternative splicing within the 5' untranslated region is affected by the (GT)n microsatellite. This data supporting an extended HMOX1 gene model and provide further insights into expression regulation of heme oxygenase-1. Alternative splicing within the HMOX1 5' untranslated region contributes to translational regulation and is a mechanistic feature involved in the interplay between genetic variations, heme oxygenase-1 expression and disease outcome.
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany ; Genome Analysis, Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kramer
authors.forename: Christoph
authors.initials: C
authors.lastname: Sponholz
authors.forename: Monique
authors.initials: M
authors.lastname: Slaba
authors.forename: Bianka
authors.initials: B
authors.lastname: Wissuwa
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Claus
authors.forename: Uwe
authors.initials: U
authors.lastname: Menzel
authors.forename: Klaus
authors.initials: K
authors.lastname: Huse
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
mesh_terms: D020121:5' Untranslated Regions; D017398:Alternative Splicing; D001483:Base Sequence; D005091:Exons; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007438:Introns; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D020121:5' Untranslated Regions; D006427:Hemin; D008156:Luciferases; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1